Dry acid concentrate in granulate form

ABSTRACT

The present invention relates to a novel dry acid concentrate (DAC) for a dialysis liquid and to a dialysis liquid, which is made from said concentrate, and which may be used for purifying blood. The invention further relates to a method of making the dry acid concentrate as well as the dialysis liquid. It also relates to a container ( 10 ) comprising said acid concentrate, and which is—in certain embodiments—specially adapted to a dialysis unit.

This application is a continuation of U.S. patent application Ser. No.15/116,947, filed Aug. 5, 2016, which is a National Stage Application ofPCT/EP2015/000251, filed Feb. 6, 2015, which claims priority to EP 14000 455.7, filed Feb. 7, 2014.

FIELD OF THE INVENTION Introduction

The present invention relates to a novel dry concentrate suitable toform a liquid acid concentrate or a part of a liquid acid concentratefor a dialysis liquid and to a dialysis liquid, which is made from saidconcentrate, and which may be used for purifying blood. The inventionfurther relates to a method of making said dry concentrate as well asthe dialysis liquid. It also relates to a container (10) comprising saidacid concentrate, and which is—in certain embodiments—specially adaptedto a dialysis unit.

BACKGROUND OF THE INVENTION

A so-called acid concentrate is usually used in the manufacture of adialysis solution in addition to a base concentrate comprisingbicarbonate. The acid concentrate comprises a solution of a plurality ofcomponents which are usually present in different amounts and/orconcentrations. Typical components are NaCl as the main component andthe other electrolytes such as KCl, CaCl₂ and MgCl₂ in smaller amounts.The dry concentrate may comprise NaCl and the other three electrolytesin a ratio of about 9 to 1. The acid concentrate may also containglucose and a pH-adjusting agent, e.g. an organic acid, such a citricacid. The specifications for the concentrations of the electrolytes arevery tight, which has the consequence that all the components of theacid concentrate have to be completely dissolved before the use of theacid concentrate in the proportioning or metering unit for manufacturingthe dialysis solution. This cannot take place in flow as with the baseconcentrate. It is rather the case that special mixing apparatus such asstirrers have to be used here to ensure this complete dissolving in anacceptable time period.

Against this background, the named acid concentrate is usually suppliedas a liquid concentrate in a canister from which the liquid concentrateis removed by means of the dialysis- or a preparation unit and is usedfor manufacturing the finished dialysis solution. A disadvantage in theuse of such canisters is the comparatively complex handling as well asthe relatively high weight, which brings about disadvantages withrespect to the transportation and storage costs as well as with regardto the handling of the same for the clinic personal.

In clinics in which a larger number of treatment stations are present,ring lines are sometimes also used which are connected to a centralsupply unit. The acid liquid concentrate is manufactured or madeavailable with the aid of special mixing apparatus in this centralsupply unit and is then fed into the ring line. It is led off from thering line at the dialysis unit or at the treatment stations and is thenavailable to the dialysis unit for preparing the ready-to-use dialysissolution. In this procedure no problems with regard to the compositionand the mixing occur. One disadvantage of this procedure is that thedisinfection and cleaning of such a system is laborious, expensive andpollutive and moreover that this type of concentrate supply is onlyeconomical for larger treatment centers due to the relatively highcosts.

One solution for the above-referenced problem is disclosed in WO2013/004362 of the present applicant. It relates to a containercontaining at least one dry concentrate, wherein the dry concentrate isof such a nature that, when it is dissolved in a liquid, e.g. in water,it forms at least one acidic liquid concentrate or part of an acidicliquid concentrate that is suitable for producing at least one dialysissolution. The container is adapted such that it can be connected to thedialysis unit via one or more connecting means. A further solution isdisclosed in WO 2011/073274, again of the present applicant. It relatesto a method of dissolving/mixing of a concentrate in/with a fluid in amulti-chamber bag, to a method for the production of a ready-to-usemedical fluid, in particular a dialysis fluid, in a multi-chamber bagand to the multi-chamber bag itself.

Solid compositions for the preparation of dialysis solutions in granularform are also known in the art. In this regard, reference is made to US2007/023139, which relates to a solid pharmaceutical preparation fordialysis, which comprises two solid pharmaceutical preparations (A) and(B), wherein pharmaceutical preparation (A) contains one or moreelectrolytes selected from the group consisting of sodium chloride,calcium chloride, magnesium chloride, and potassium chloride and anorganic acid other than acetic acid and/or a salt of the organic acid,and wherein the solid pharmaceutical preparation (B) contains sodiumbicarbonate. This preparation is prepared by a spray-drying granulationprocess.

EP 1 120 110 relates to a composition for the preparation of a dialyticsolution which contains all the components or ingredients known per seand used for the preparation of the acid solution and the basic solutionto be used in dialysis, wherein these ingredients form part of at leastone granulate in which the ingredients are present in predetermined andconstant ratios.

Further preparations to be used for dialysis in the form of a granulateare disclosed in U.S. Pat. No. 6,210,803, EP 0 417 478 and EP 2 151 247,which compositions respectively contain granulates made of granuleswhich respectively contain all electrolytes required for a ready-to-usesolution for hemodialysis.

The introduction of water to the granular preparations according to theprior art leads to the formation of hardly soluble particles, which ledto problems with the accuracy of the exact ratio of constituents neededin the dry concentrate or at least significantly enhance the time ofdissolution.

In view of the above situation, it is one object of the presentinvention to provide a dry concentrate suitable to form a liquid acidconcentrate or a part of a liquid acid concentrate having improveddissolution characteristics in order to even further ensure that theresulting dialysis liquid contains the necessary constituents in thephysiologically necessary amounts and proportions to each other.

It is another object to provide a dry concentrate suitable to form aliquid acid concentrate or a part of a liquid acid concentratecomprising all necessary constituents in the necessary relative amountswithout elaborate weighing procedures, which would be the case when allconstituents are to be weighed individually.

It is another object to provide a dry concentrate suitable to form aliquid acid concentrate or a part of a liquid acid concentrate that canbe provided ready-to-use within a dialysis unit for one treatment of onepatient.

It is a further object to provide a liquid acid concentrate in a mannerto avoid the transport of heavy canisters and/or the provision ofcomplex ring line systems, stated differently, it was an object toprovide a dry concentrate suitable to form a liquid acid concentrate ora part of a liquid acid concentrate in an appropriate form for theinstantaneous preparation of dialysis solutions, in line, ready forimmediate use.

SUMMARY OF THE INVENTION

In view of the above objects, the invention provides a dry concentratesuitable to form a liquid acid concentrate or a part of a liquid acidconcentrate usable in dialysis comprising

a first component comprising a first granulate comprising a plurality offirst granules comprising sodium chloride and glucose, and

a second component comprising a second granulate comprising a pluralityof second granules, wherein said granules comprise at least one furtherphysiologically acceptable electrolyte, which is different from sodiumchloride,

or a second component in the form of a powder, wherein said powdercomprises at least one further physiologically acceptable electrolytewhich is different from sodium chloride, and wherein said powdercomprises a plurality of fine particles, wherein each particle comprisesor consists of one of said at least one further physiologicallyacceptable electrolyte,or a mixture of said granulate and said powder.

In one embodiment of the dry concentrate the first and the secondcomponent comprise or consist of said first and second granulate.

In one embodiment of the dry concentrate the granules of the firstcomponent exhibit a higher average equivalent diameter than the granulesof the second component.

In one embodiment of the dry concentrate the first granulate comprisesat least 50 wt-%, e.g. at least 75 wt-% or. at least 90 wt-% ofgranules, respectively based on the total weight of the first granulatein the dry concentrate, which have an equivalent diameter of above 0.5to below 12.5 mm.

In one embodiment of the dry concentrate the second granulate comprisesat least 50 wt-%, e.g. at least 75 wt-% or at least 90 wt-% of granules,respectively based on the total weight of the first granulate in the dryconcentrate, which have an equivalent diameter of above 1 to below 5 mm.

In one embodiment of the dry concentrate said second component comprisesa cation selected from the cations of magnesium, calcium, potassium, ormixtures of two or more thereof; and comprises an anion selected fromchloride, acetate, lactate, or mixtures of two or more thereof, e.g.wherein the second component comprises MgCl₂, CaCl₂ and KCl.

The dry concentrate may further comprising citric acid as a thirdcomponent.

In another embodiment, the invention relates to a dry concentrate,wherein the granulates of the first component or the first and thesecond component are obtainable via a manufacturing process comprisingthe following step(s):

dry compressing said NaCl and glucose to obtain first compacts, or drycompressing said NaCl and glucose, and the at least one furtherphysiologically acceptable electrolyte to obtain first and secondcompacts, wherein said dry compressing of said first and said drycompressing of said second compacts are conducted separately from eachother;reducing the size of said first compacts to form a first granulatecomprising a plurality of first granules,or reducing the size of said first and second compacts to form a firstand second granulate comprising a plurality of first and secondgranules.

In one embodiment the separate dry compressing of the first and secondcompacts comprises the step of passing the NaCl and glucose or the NaCland glucose and the at least one further physiologically acceptableelectrolyte under pressure between two rolls with parallel axes, whichare driven in mutually counter-rotating rotation sense.

In one embodiment the reduction of size is achieved by grinding,milling, crushing, or a combination of two or more thereof.

In one embodiment said steps of dry compressing and reduction of sizeare carried out continuously.

In another embodiment, the invention relates to a process for thepreparation of the dry concentrate comprising the following step(s):

dry compressing said NaCl and glucose to obtain first compacts, or drycompressing said NaCl and glucose, and the at least one furtherphysiologically acceptable electrolyte to obtain first and secondcompacts, wherein said dry compressing of said first and said drycompressing of said second compacts are conducted separately from eachother;

-   -   reducing the size of said first compacts to form a first        granulate comprising a plurality of first granules,    -   or reducing the size of said first and second compacts to form a        first and second granulate comprising a plurality of first and        second granules.

In one embodiment the dry compressing comprises the step of passing theNaCl and glucose or the NaCl and glucose and the at least one furtherphysiologically acceptable electrolyte under pressure between two rollswith parallel axes, which are driven in mutually counter-rotatingrotation sense.

In one embodiment the reduction of size is achieved by grinding,milling, crushing, or a combination of two or more thereof.

In one embodiment said steps of dry compressing and reduction of sizeare carried out continuously.

In one embodiment said manufacturing process comprises the sieving ofsaid granulates obtained by reducing the size of said compacts throughat least two sieves, e.g. through exactly two sieves. The manufacturingprocess may include a step of re-introducing the granules having a sizeabove a desired maximum equivalent diameter or below a desired minimumequivalent diameter into said compressing step. In one embodiment itincludes a step of re-introducing all granules into said compressingstep.

In another embodiment, the invention relates to a container (10)comprising at least the dry concentrate according to the invention.

In one embodiment, said container (10) is designed such that it has atleast one connection means (12) by means of which the container (10) canbe coupled to a dialysis unit or to a preparation unit for an acidliquid concentrate.

In one embodiment the container (10) may comprise the first and secondand optionally third component in separate compartments. It may alsocomprise the first and the second component in one compartment and, ifpresent, the third component in a second compartment. It may alsocomprise the first, the second and the third component, if present, inone compartment. In one embodiment, these compartments or thiscompartment contains only said first and/or second and/or thirdcomponent, i.e. besides those components no additional constituents arepresent.

In one embodiment, the container (10) has at least one introductionmeans (16) by which at least one liquid, e.g. water, or at least oneliquid, e.g. water, and a gas, e.g. air, can be introduced into thecontainer (10) for the purpose of dissolving the dry concentrate (20),with the introduction means (16) being formed as a hose or at leastcomprising a hose.

In one embodiment, the introduction means (16) is dimensioned such thatit projects up to and into the dry concentrate (20).

In one embodiment said at least one introduction means (16) projects,starting from an upper container wall, from above into the interior ofthe container (10) and down to and into the bottommost point of theinner space of the container (10) and ends close to the bottommost pointof the container (10), e.g. 5 (±3) mm above said bottommost point of thecontainer (10), wherein said bottommost point of the container (10) islocated along the wall opposite to the introduction means (16). Saidintroduction means may be in the form of a hose.

In one embodiment, the container (10) has wall regions (17, 18) whichface toward one another in at least one region and between which atrough-shaped region (19) or a recess is formed, with the dryconcentrate (20) being at least also present in the trough-shaped region(19) or in the recess in the operating position of the container (10),e.g. wherein the inclined wall regions (17,18) form an angle between 30°and 70°, or 40° to 60°, in particular 50° between each other.

In one embodiment, the container (10) has the following characteristics:

it comprises at least one connection means (12) by means of which thecontainer (10) can be coupled to a dialysis- or to a preparation unitfor an acid liquid concentrate;

it comprises at least one introduction means (16) in the form of a hose,which projects, starting from an upper container wall hosting theintroduction means (16), from above into the interior of the container(10) and down to and into the bottommost point of the inner space of thecontainer (10) and ends 5 (±3) mm above said bottommost point of thecontainer (10), and wherein said bottommost point of the container (10)is located along the wall opposite to the introduction means (16); andthe container (10) has wall regions (17, 18) which face toward oneanother in at least one region and between which a trough-shaped region(19) or a recess is formed, with the dry concentrate (20) being at leastalso present in the trough-shaped region (19) or in the recess in theoperating position of the container (10), wherein the inclined wallregions (17,18) form an angle between 30° and 70°, in particular 50°between each other.

In one embodiment, the container (10) is made as a stand-up container.

In one embodiment, the container (10) has at least two films orprecisely two films, which form the container walls, with one of thefilms having a folded section in the empty state of the container (10),which forms a container wall in the filled state of the container (10).

In one embodiment, the container (10) as such, i.e. without the dryconcentrate, is adapted to contain a dry concentration of the inventionand has the following characteristics:

it comprises at least one connection means (12) by means of which thecontainer (10) can be coupled to a dialysis- or to a preparation unitfor an acid liquid concentrate;

it comprises at least one introduction means (16) in the form of a hose,which projects, starting from an upper container wall hosting theintroduction means (16), from above into the interior of the container(10) and down to and into the bottommost point of the inner space of thecontainer (10) and ends 5 (±3) mm above said bottommost point of thecontainer (10), and wherein said bottommost point of the container (10)is located along the wall opposite to the introduction means (16); andthe container (10) has wall regions (17, 18) which face toward oneanother in at least one region and between which a trough-shaped region(19) or a recess is formed such that a dry concentrate (20) can be alsopresent in the trough-shaped region (19) or in the recess in theoperating position of the container (10), wherein the inclined wallregions (17,18) form an angle between 30° and 70°, e.g. 50° between eachother.

In one embodiment, the container (10) contains the dry concentrate inthe appropriate amount for one dialysis treatment of one patient.

In another embodiment, the invention relates to a dialysis orpreparation unit, wherein the preparation unit serves to prepare aliquid concentrate to be used for the preparation of a dialysissolution, comprising at least one dry concentrate of the invention. Thedialysis or preparation unit may also comprise one or more of thecontainers (10) as described within the invention, wherein the container(10) is connected to the dialysis or preparation unit.

In another embodiment, the invention relates to a method of preparing aliquid acid concentrate which in turn serves the preparation of adialysis solution, at least comprising step (i) of mixing the dryconcentrate with water.

In one embodiment, said step (i) is carried out in the presence of agas, e.g. air.

In one embodiment, said mixing is carried out under at least one of thefollowing conditions, in one embodiment under a combination ofconditions 2), 5) and 6):

-   -   1) the mixing is carried within the container (10) of the        invention;    -   2) the mixing is carried within a container (10) with the        following characteristics:        -   it comprises at least one connection means (12) by means of            which the container (10) can be coupled to a dialysis- or to            a preparation unit for an acid liquid concentrate;        -   it comprises at least one introduction means (16) in the            form of a hose, which projects, starting from an upper            container wall hosting the introduction means (16), from            above into the interior of the container (10) and down to            and into the bottommost point of the inner space of the            container (10) and ends 5 (±3) mm above said bottommost            point of the container (10), and wherein said bottommost            point of the container (10) is located along the wall            opposite to the introduction means (16); and        -   the container (10) has wall regions (17, 18), which face            toward one another in at least one region and between which            a trough-shaped region (19) or a recess is formed such that            a dry concentrate (20) can be also present in the            trough-shaped region (19) or in the recess in the operating            position of the container (10), wherein the inclined wall            regions (17,18) form an angle between 30° and 70°, e.g. 50°            between each other;    -   3) the mixing is carried out in the presence of water and air,        wherein water is added to the container (10) with a velocity of        600 to 800 ml/min;    -   4) the mixing is carried out in the presence of water and air,        wherein air is added to the container (10) with a velocity of 1        to 3 l/min;    -   5) the mixing is carried out in the presence of water and air,        wherein water is added to the container (10) with a velocity of        600 to 800 ml/min and air is added to the container (10) with a        velocity of 1 to 3 l/min;    -   6) the mixing is carried out at a temperature of from 50° C. to        65° C., e.g. 55° C. to 60° C.

In one embodiment, the method of preparing a liquid acid concentrate iscarried out such that a complete dissolution of the concentrate isachieved within less than 10 minutes, e.g. in 5 to less than 10 minutes,or 7 to 9 minutes.

In one embodiment, said method is carried out within the dialysis orpreparation unit at a point in time, where no dialysis takes place.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the invention is directed to a dry concentratesuitable to form an acid liquid concentrate or a part of an acid liquidconcentrate usable in dialysis.

The term “dry concentrate” as used herein means that in the concentrate,if at all, only minor amounts of water are present. The water amount maybe less than 10 wt.-%, e.g. less than 5 wt.-%, based on the total amountof concentrate.

Said dry concentrate is one that is “suitable to form an acid liquidconcentrate or a part of an acid liquid concentrate”. This term does notprovide a significant limitation for the dry concentrate of the presentinvention and rather sets out that said dry concentrate can and in factshould be mixed with water with the aim to provide a (part of) an acidliquid concentrate, which in turn is useable for dialysis purposes, inparticular as one constituent of the dialysis solution to be applied tothe patient. It, however, provides a limitation in that the dryconcentrate is substantially free of any base components, which aresuitably used in dialysis, such as sodium bicarbonate. In oneembodiment, the first and the second component are respectively alsosubstantially free from any acid components that are suitably used indialysis. In another embodiment, the first and/or the second componentare substantially free of any base components, which are suitably usedin dialysis, but additionally comprise an acid component, such as citricacid. In a further embodiment, said additional acid component iscontained in said second component. In the context of the presentapplication, the term “substantially free” means that the amounts ofbase and/or acid component in said dry concentrate, e.g within the firstand/or second granulate, are such that without the addition ofadditional base and/or acid component no dialysis solution can beprepared. In one embodiment, the dry concentrate is free of any basecomponents. In another embodiment, the first and second component arefree of any acid components. In another embodiment, the first and secondcomponent are free from any base component, but one of the twocomponents comprises the acid component.

The dry concentrate comprises a first component comprising a firstgranulate, which comprises a plurality of first granules comprisingsodium chloride and glucose.

It further comprises a second component comprising a second granulate,which comprises a plurality of second granules, which respectivelycomprise at least one, e.g. at least two, e.g. three furtherphysiologically acceptable electrolytes, which are different from sodiumchloride. In one embodiment the second component comprises a powdercomprising a plurality of fine particles, wherein each of said fineparticles comprises or consists of one of said further physiologicallyacceptable electrolyte, which is different from sodium chloride. Thesecond component may also be a mixture of said second granulate and saidpowder.

The term “component” as used herein means a part of the concentrate.

The term “granulate” as used herein relates to a plurality of granuleswhich form the granulate. The term “granule” is used herein in itsbroadest meaning and relates to a small particle that is gathered intoan aggregate, wherein the individual particle size of the particle canstill be determined. The granulate may contain a plurality of granuleswhich are heterogeneous or homogeneous in size. The granules of thefirst and the second component, respectively comprise at least twoconstituents, namely NaCl and glucose (first granules) and at least one,e.g. at least two, e.g. three further physiologically acceptableelectrolytes being different from NaCl (second granules). For preparingthe granulate any manufacturing process known in the art may be used.The first and the second granulate are different from each other. Thisis immediately apparent from claim 1 itself, which stipulates thedifference between the electrolytes within the granulates. However, thefirst and the second granulate may be different from each other infurther aspects, such as size, shape and method of manufacture.

The term “powder which comprises at least one further physiologicallyacceptable electrolyte which is different from sodium chloride”, as usedherein, and denoted hereinunder also as “powder”, relates to a dry, bulksolid composed of a large number of very fine particles that may flowfreely when shaken or tilted. Each individual fine particle comprises orconsists of only one of said further physiologically acceptableelectrolytes.

The first granulate comprises a plurality of first granules comprisingNaCl and glucose. In one embodiment the first granulate consists of saidplurality of first granules. In a further embodiment the first granulescomprise 50 to 100 wt-%, e.g. 75 wt-% or more or 90 wt-% or more of NaCland glucose. In a still further embodiment the first granulate consistsof a plurality of first granules, which comprise 50 to 100 wt-%, e.g. 75wt-% or more or 90 wt-% or more of NaCl and glucose.

In one embodiment the first granules comprises no other activeconstituent suitably used for a dialysis solution/dry concentrate apartfrom NaCl and glucose. In this embodiment, other constituents, such asbinders, may be present in said first granules. Thus, it is also withinthe ambit of the present application to provide a granulate suitable tobe used as a component within a dry concentrate as defined herein, whichcomprises a plurality of granules, which comprise NaCl and glucose asthe only active constituents of a dialysis solution. In one embodimentthese first granules consist of NaCl and glucose.

The second granulate comprises a plurality of second granules, which inturn comprises at least one, e.g. at least two, e.g. three furtherphysiologically acceptable electrolytes, which are different from sodiumchloride. In one embodiment the second granulate consists of saidplurality of second granules. In a further embodiment the secondgranules consist of 50 to 100 wt-%, e.g. 75 wt-% or more or 90 wt-% ormore of said at least one, e.g. at least two, e.g. three furtherphysiologically acceptable electrolytes. In a still further embodimentthe second granulate consists of a plurality of second granules, whichcomprise 50 to 100 wt-%, e.g. 75 wt-% or more or 90 wt-% or more of saidat least one, e.g. at least two, e.g. three further physiologicallyacceptable electrolyte.

In a further embodiment, the second component comprises a powdercomprising at least one further physiologically acceptable electrolyte,which is different from sodium chloride. Said powder comprises aplurality of fine particles, wherein each of said fine particlescomprises or consists of one of said further physiologically acceptableelectrolytes. In a further embodiment the fine particles consist of 50to 100 wt-%, e.g. 75 wt-% or more or 90 wt-% or more of said one furtherphysiologically acceptable electrolyte. In a still further embodimentthe second components consists of said powder, which comprise 50 to 100wt-%, e.g. 75 wt-% or more or 90 wt-% or more of said at least onefurther physiologically acceptable electrolyte.

In a further embodiment the dry concentrate comprises the first and thesecond component in the form of said first and second granulates.

In one embodiment the granules within the first and second granulate arepredominantly irregularly-shaped, i.e. not round particles. In thisembodiment, the granules of the first component exhibit a higher averageequivalent diameter than the granules of the second component.

The term “average equivalent diameter” or “equivalent diameter” refersto (the average of) the diameter of an irregularly-shaped object, here,granule or fine particle, that corresponds to the diameter of aspherical particle as determined by sieving through a sieve with roundholes. Granules having an “equivalent diameter in the range of above 0.5to below 12.5 mm” are granules that are able to pass through a sievewith holes having a diameter of 12.5 mm in any orientation, but areunable to pass a sieve having holes with a diameter of 0.5 mm in someorientation. The term “equivalent diameter” is used herein for irregularand regular, i.e. round or spherical particles, respectively. Needlessto say that for spherical granules and fine particles the equivalentdiameter corresponds to their diameter.

The same relation also applies in cases where the granules arepredominantly round and the dimensions of the granules may be determinedvia their diameter; i.e. the average diameter of the granules of thefirst granulate is higher compared to those of the second granulate.

This difference in average particle size between the first and thesecond component has the advantage of a still further improveddissolution profile in water such that all constituents within the dryconcentrate may be dissolved concurrently. The exact size and sizedifference necessary to optimize the dissolution behavior of the firstand second component may be determined by the person skilled in the artbased on routine experimentation.

In one embodiment the first granulate comprises at least 50-wt-%, e.g.at least 75-wt-% or e.g. at least 90-wt-% of granules having anequivalent diameter in the range of above 0.5 to below 12.5 mm, e.g.above 0.8 to below 8.0 mm. In a further embodiment up to 100 wt-% of thefirst granules within the first granulate fulfill this equivalentdiameter range.

In another embodiment the second granulate comprises at least 50%, e.g.at least 75% or e.g. at least 90% of granules having an equivalentdiameter in the range of above 1 to below 5 mm, e.g. above 1.2 to below4.8 mm. In a further embodiment up to 100 wt-% of the second granuleswithin the second granulate fulfill this diameter range.

In one embodiment the first and/or the second granulate may comprisegranules that are not within the specification, and which are smaller inequivalent diameter than the specification requires. In one embodimentat least 80 wt-% of the total of the granules that are not within thespecification exhibit an equivalent diameter that is smaller than thelower limit of the specification.

In a still further embodiment the first and the second granulate bothfulfill the above mentioned conditions as to their size in terms of theequivalent diameter.

The first component comprises NaCl and glucose. The glucose may bepresent in the first component in the form of its monohydrate or inanhydrous form. The term also encompasses D-glucose (also denoted asdextrose) and L-glucose as well as racemates of D- and L-glucose. It mayfurther comprise additives such as pH adjusting agents.

The second component comprises at least one of the further electrolytesnecessarily to be used in an acid dialysis solution.

The term “electrolyte” as used herein, comprises all electrolytes, whichdo not cause intolerances or adverse effects in and at the patientsduring dialysis.

In one embodiment, the physiologically acceptable electrolyte hascations selected from the cations of magnesium, calcium, potassium, orfrom mixtures of two or more thereof. Within this embodiment, the anionsmay be selected from chloride, acetate, lactate, or two or more of theseanions.

In one embodiment, as physiologically acceptable electrolyte, salts areused selected from: calcium chloride, magnesium chloride, calciumlactate, magnesium lactate, calcium acetate, magnesium acetate, or fromcombinations of two or more thereof.

In one embodiment, the first component in the form of a granulatecomprises NaCl and glucose, and the second component comprises CaCl₂,MgCl₂ and KCl and is also in the form of a granulate.

In another embodiment the concentrate comprises a third component whichmay be citric acid or another suitable acid, e.g. citric acid.

According to a second aspect the invention relates to a process ofpreparing the dry concentrate. This process encompasses the provision ofthe first component in the form of a first granulate and the provisionof the second component in the form of a second granulate or a powder.

Thus, the process comprises a granulating step. Therefore, the processof preparation of the first and second component in the form of agranulate comprises the weighing out/provision of the constituentsindividually and forming a first and a second granulate. The first andthe second granulate may be obtained by separately granulating/preparingthe same and forming the dry concentration by combining, e.g. mixing,the two separately prepared granulates.

Within the ambit of the present invention any kind of granulationincluding dry and wet granulation methods known in the art may be used,such as fluidized-bed granulation, agitating granulation, pan coatingand wet granulation. With regard to further details as to the methods ofgranulation available to prepare the granulates of the dry concentrateparticular reference is made to U.S. Pat. No. 6,210,803 by theapplicant, as well as EP 2 151 247 and EP 0 602 014.

In one embodiment, the granulation process as disclosed in EP 0 287 978is used. Compared to the fluidized bed granulation well known in theart, this granulation method is significantly more economical, e.g. interms of energy consumption. The granulation process according to EP 0287 978 is a continuous process, wherein the components are continuouslyprovided into the granulation means.

Thus, the present application relates to process for the preparation ofthe dry concentrate as described herein comprising the followingstep(s):

-   -   dry compressing said NaCl and glucose, or the at least one        further physiologically acceptable electrolyte, or said NaCl and        glucose, and the at least one further physiologically acceptable        electrolyte to obtain first and second compacts, wherein said        dry compressing of said first and said dry compressing of said        second compacts are conducted separately from each other;    -   reducing the size of said first compacts to form a first        granulate comprising a plurality of first granules, or reducing        the size of said first and second compacts to form a first and        second granulate comprising a plurality of first and second        granules, or reducing the size of the first compacts to form a        first granulate comprising a plurality of first granules and        reducing the size of the second compacts to form a powder.

In one embodiment the dry compressing comprises the step of passing saidNaCl and glucose or said NaCl and glucose and the at least one furtherphysiologically acceptable electrolyte under pressure between two rollswith parallel axes, which are driven in mutually counter-rotatingrotation sense.

The reduction of size may be achieved by any method known in the art,such as grinding, milling, crushing, or a combination of two or morethereof.

Furthermore, said steps of dry compressing and reduction of size arecarried out continuously.

In a further embodiment said preparation process comprises the sievingthrough at least two sieves, in one embodiment through exactly twosieves, of said granulates obtained by reducing the size of saidcompacts. In a further embodiment the granules having a size above thedesired maximum size or below the desired minimum size are re-introducedinto said compressing step. In a further embodiment all granules arere-introduced into said compressing step. This sieving andre-introduction into the compressing step may be carried out severaltimes and leads to a more homogeneous size distribution of the granuleswithin the granulates. It also minimizes the amount of in someembodiments unwanted very small particles (dust) and, generally, ofgranules having a size outside the specification

In addition, the invention also relates to a dry concentrate obtainableby the method of preparation defined hereinbefore, namely a dryconcentrate comprising a first component in the form of a firstgranulate as defined hereinabove and a second component in the form of asecond granulate or a powder, as respectively as defined hereinabove,wherein the first and/or the second granulate are obtained via agranulation procedure.

In one embodiment, the invention relates to a dry concentrate as definedhereinabove, wherein the granulates of the first or the second componentor the first and the second component are obtainable via a manufacturingprocess comprising the following step(s):

-   -   dry compressing said NaCl and glucose, or the at least one        further physiologically acceptable electrolyte, or said NaCl and        glucose, and the at least one further physiologically acceptable        electrolyte to obtain first and second compacts, wherein said        dry compressing of said first and said dry compressing of said        second compacts are conducted separately from each other;    -   reducing the size of said first compacts to form a first        granulate comprising a plurality of first granules, or reducing        the size of said first and second compacts to form a first and        second granulate comprising a plurality of first and second        granules, or reducing the size of the first compacts to form a        first granulate comprising a plurality of first granules and        reducing the size of the second compacts to form a powder;    -   e.g. wherein the dry compressing comprises the step of passing        the NaCl and Glucose or the NaCl and glucose and the at least        one further physiologically acceptable electrolyte under        pressure between two rolls with parallel axes, which are driven        in mutually counter-rotating rotation sense; and/or    -   e.g. wherein the reducing of size is achieved by grinding,        milling, crushing, or a combination of two or more thereof;        and/or    -   e.g. wherein said steps of dry compressing and reduction of size        are carried out continuously.

The resulting dry concentrate may be provided in a one-piece form or ina multi-part form, for example in a two-part form or in a three-partform. This means that the two or three components of the dry concentratemay be provided as a mixture of all components, e.g. within a container(10) comprising only one compartment, or may be provided in separatecompartments of a container (10) or in separate containers (10),respectively.

In one embodiment, the first and the second component are providedwithin one compartment of a container (10) or in one container (10),while the third component, i.e. the citric acid, is provided in aseparate compartment of the same container (10) or is contained within aseparate container (10).

In a third aspect the invention relates to a liquid acid concentratebeing prepared from said dry concentrate. In order to arrive at a liquidconcentrate, the dry concentrate of the subject invention has to beadmixed with water, e.g. ultrapure water. This is achieved by meansknown in the art, e.g. in a dialysis or preparation unit prior tostarting the dialysis.

In a fourth aspect the invention relates to a container (10) comprisingthe dry concentrate of the invention.

The term “container” as used herein encompasses terms such as“packaging” or “bag” or “cartridge”. In one embodiment, the term“container” means also a container, which, e.g., may be removed from adialysis unit or a device, which is connected to a dialysis unit, andmay be reinserted into said unit. In a further embodiment, the term“container” means also that said container is accessible for waterand/or a physiologically acceptable electrolyte solution, e.g. a sodiumchloride solution, in order to dissolve the components, which arepresent in the container (10), and/or to release protons from them.

In said embodiments, the container (10) has typically such a volumethat, in addition to the dry concentrate, liquid, e.g. water, can bereceived or is received in a volume of 1 to 15 liters or 2 to 14 liters,or 3 to 13 liters, or 4 to 6 liters, to manufacture the acid liquidconcentrate by dissolving the dry concentrate and/or that the container(10) has a total volume in the range from 1 to 15 liters or 2 to 14liters, or 3 to 13 liters, or 4 to 6 liters.

The dry concentrate can be present in the container (10) in an amount of0.5 kg to 6 kg, e.g. in an amount of 0.75 kg to 5.5 kg, further e.g. inan amount of 1.0 kg to 5.0 kg, and particularly e.g. in an amount of 1.3to 4.2 kg. Such containers (10) allow a problem-free handling, are easyto transport and to store and are suitable for carrying out one or morehemodialysis treatments.

It is possible that the dry concentrate is composed such that the acidliquid concentrate obtained on its dissolution in a volume of 2 to 15liters, or of 4 to 15 liters has a pH<7.0.

It is in particular conceivable that the dry concentrate is contained inthe container (10) in a quantity such that on its dissolution in avolume of 4 to 15, e.g. 4 to 6 liters of liquid, e.g. water, a liquidconcentrate results, with the dry concentrate e.g. being completelydissolved.

Generally, the dissolution for manufacturing the finished dialysissolution is performed in situ, and the amount and proportions of theconstituents of the components as well as the container size and amountof water is adjusted such that the constituents are e.g. present in thefollowing concentration ranges (in mmol/l) with respect to the volume ofthe finished dialysis solution:

NaCl: 110-170 mmol/l, e.g. 130-150 mmol/l KCl: 0.7-4.3 mmol/l, e.g.1.0-4.0 mmol/l CaCl₂: 0.7-2.0 mmol/l, e.g. 1.0-1.7 mmol/l MgCl₂: 0.3-1.2mmol/l, e.g. 0.5-1.0 mmol/l Glucose: 0.8-2.2 g/l, e.g. 1.0-2.0 g/lCitric acid: 0.1-20  mmol/l, e.g.  1.0-15.0 mmol/l,

All values relate to the finished dialysis solution. It is, for example,conceivable that 34 liters of a mixture of water and the baseconcentrate are mixed with 1 liter of the acid liquid concentrate toobtain 35 liters of ready-to-use dialysis solution. This mixing rationaturally applies not only to the above-named example, but can beassumed as a suitable mixing ratio in general.

The below table shows typical embodiments of the concentration (inmmol/l) of the relevant constituents stemming from the dry concentrateof the subject invention in the (ready-to-use) dialysis solution as wellas the liquid acid concentrate in various concentration grades.

Concentration of the Concentration Concentration Concentrationconstituents in the within the within the within the dialysis solutionliquid acid liquid acid liquid acid stemming from the concentrateconcentrate concentrate acid concentrate 30-fold 45-fold 37-fold Na+ 1033090 4635 3811 Cl— 110 3300 4950 4070 Ca2+ 1.5 45 67.5 55.5 Mg2+ 0.5 1522.5 18.5 K+ 2 60 90 74 K+ 3 90 135 111 K+ 4 120 180 148 Citric acid 130 45 37

For preparing the dialysis solution, typically 35 mmol/l sodiumbicarbonate are added, which results in a sodium concentration withinthe dialysis solution of 138 mmol/l. The mixing ratios within the devicefor preparing the (ready-to-use) dialysis solution are 1 part acidconcentrate, 1.6 to 3.3 parts base concentrate, typically a saturatedsodium bicarbonate solution, and about 30 to about 40 parts water.

In one embodiment, the amount and ratio of components within said dryconcentrate are used such that together with the appropriate amount ofwater a liquid acid concentrate results that is suitable to be used forone treatment of one patient. Within this embodiment, the container (10)comprising the appropriate amounts of a first and second and optionallythird component is filled with a total amount of water of 4157 ml. Theresulting liquid concentrate is diluted within the dialysis orpreparation unit in a ratio of 1:37. Water is added to the container(10) with a velocity of 600 to 800 ml/min, e.g. 700 ml/min together withair at a velocity of 1 to 3 l/min, e.g. 2 l/min. In one embodiment saiddissolution is carried out at a temperature in the range of 50 to 65° C.Further details regarding the provision of such a liquid concentrate forone treatment of one patient may also be deduced from the examplehereinafter.

Particularly suitable containers (10) are disclosed in WO 2013/004362and WO 2013/020989, whose contents are incorporated herein by reference.Besides the container material and shape, WO 2013/020989 also disclosessuitable connection means to connect the container (10) to the dialysisor preparation unit as well as introduction means for water and/or airnecessary to reliably and quickly provide a liquid acid concentrate.

As to the shape of the container (10), in particular to the sectionopposite to the connection means (12) with the wall region (17, 18)facing towards each other and forming a trough shaped region (19)reference is made to FIG. 1 of WO 2013/020989 and the correspondingdescription.

In one embodiment, the container (10) is fixedly connectable to thedialysis- or to a preparation unit. As to the corrector means referencein made again to WO2013/004362 and the prior art cited therein.

In another embodiment, the container (10) may also include the baseconcentrate, however, in any case in a separate compartment.

In one embodiment not only water, but also air, is introduced throughthe connection means of the container (10) and through the couplingmeans of the dialysis- or of the preparation unit or through acorresponding fluid connection of these means/unit, and further e.g.through a hose or the like, into the container (10) for the purpose ofdissolving the dry concentrate. Respective connector means are known inthe art and e.g. disclosed in EP 1 344 550 B1.

Deviating from the teaching of EP 1 344 550 B1, provision is e.g. madewithin the framework of the present invention that a connector partserves for the supply of air and of the solvent, in particular water, aswell as also for the removal of the liquid concentrate. The otherconnector part serves, within the framework of the present invention,only for the removal of gas or air from the container (10).

Provision can furthermore be made that the container (10) has at leastone coding by means of which the container (10) and/or the dryconcentrate and/or the liquid acid concentrate can be identified.

As to further details regarding the coding, the venting, outlet andintroduction means, again reference is made to WO 2013/04263.

One particular embodiment of the container (10) according to the fourthaspect of the invention is now described with regards to the figures.There are shown:

FIG. 1: a schematic view of a container (10) in accordance with theinvention which is partly filled with dry concentrate;

FIG. 2: a perspective view of a receptacle in accordance with theinvention as well as a coupling region of a dialysis- or of apreparation unit before the coupling of the receptacle;

FIG. 3: a schematic view of an embodiment of the container (10) inaccordance with the invention during manufacture and well as during theopening procedure;

FIG. 4: a longitudinal sectional view through a container (10) inaccordance with the invention as well as a perspective view of thecontainer (10) in accordance with the invention;

FIG. 5: a plan view of the film web for manufacturing the container(10);

FIGS. 6, 7: schematic representations of the manufacturing process.

FIG. 1 shows a schematic view of the container 10 in the operatingposition. Two wall sections 17, 18 are located which are both designedas sloping with respect to the horizontal and are made fallingrespectively from the outside to the inside and form a trough-shapedregion 19 between them, which in turn forms the bottommost point orregion in which the dry concentrate is located in the inner containerspace.

Thus, the container 10 has wall regions 17, 18 between which atrough-shaped or depression-shaped region 19 forms, with the dryconcentrate 20 being at least also present in the trough-shaped region19 in the operating position of the container 10. It can be ensured inthis manner that the dry concentrate “slides on” into the namedtrough-shaped region 19 and is thus present at a central position inwhich favorable conditions apply for the dissolving of the dryconcentrate. In the preferred embodiment, the value of the angle betweenthe wall regions 17 and 18 is 50° as indicated in FIG. 1. Alsocontainers 10 having inclined wall regions 17, 18 with an angle of 30°to 90°, e.g. 40° to 60°, such as 50° there between realize theadvantageous effect of the depression-shaped region 19.

Provision is thus e.g. made that the container 10 has at least one, or aplurality of funnel-like constrictions, and indeed in the lower endregion of the container 10. It is thus ensured that the non-dissolveddry concentrate is located directly at the point of delivery of thefluid or liquid and air during the total dissolving procedure and is tocontinuously swirled. The time for the complete dissolving of theconcentrate is in particular reduced to a favorable time period by thismeasure.

The introduction means 16, i.e. the hose, the line or the like, e.g.extends up to and into the trough-shaped region 19 or up to and into thefunnel-like constriction. The distance D between the lower end of thepipe 16 and the bottommost point of the container 10 of a preferredembodiment is about 5 mm, e.g. 5 mm+/−3 mm. Also containers 10 havingdistances D of 2 mm to 8 mm between the lower end of the pipe 16 and thebottommost point of the container 10 allow an effective operation of thecontainer 10.

As can further be seen from FIG. 1, the container 10 is not completelyfilled with one type of concentrate 20. The dry concentrate comprisesthe following substances: electrolytes, glucose and citric acid oranother suitable acid in solid or liquid form. In a preferredembodiment, about 90% of the container is filled with NaCl/dextrosegranules 20 a which is optimized for dissolution. Upon this concentrate,minor granules 20 b are filled, which is optimized for excellenthomogeneity.

The container 10 is connected my means of a connection element 12 whichwill be described later. In one embodiment, at the top of the container10 a tank 10 c is arranged with an opening mechanism which can be arigid piston with cutting shape or also a piercable membrane when usinga soft tank or the like. Within the tank 10 c a citric acid 20 c isstored, e.g. in powder form. Within FIG. 1 this mechanism is alreadyopen. In another embodiment, the constituents 20 a to 20 c are stored insaid container 10 without any opening mechanism, i.e. the constituents20 a to 20 c are present in one compartment.

The bag 10 has a special connection element 12 in its region shown atthe top in the Figure with which the bag can be suspended at a dialysisunit or at a filling station which is also called a preparation unitwithin the framework of the present invention. The connection element 12can be made such that it can be connected, e.g. in a fluid-tight and/orgas-tight manner, to a special coupler of the dialysis- or of apreparation unit. This connection can be established, for example, by asimple plugging on or by a rotary movement or by a screw connection.

After establishing this connection, liquid and/or gas can be introducedinto the container 10 by means of the line 16. As soon as the dryconcentrate is completely dissolved, the acid liquid concentrate canlikewise be drawn out of the container 10 by means of the line 16. Theline 16 projects, starting from an upper container wall, from above intothe interior of the container 10 and down to and into the lowest pointof the inner space of the container 10 or into the dry concentratepresent there.

As can further be seen from FIG. 1 the bag has an inflow 16 which isformed in the manner of a hose 16 and whose open end lies at theabove-named lowest point 19 of the container 10. The inflow or the hose16 is provided in its end region projecting into the container 10 with afilter or the like as protection to prevent the penetration of the dryconcentrate into the interior of the hose 16.

The filling with water, the introduction of air and the drawing off ofthe liquid concentrate takes place through the line 16. The producedliquid concentrate can be mixed with a volume of water, e.g. RO water,to be able to produce the finished dialysis solution. The base liquidconcentrate, which can likewise be obtained by dissolving a dryconcentrate in a container 10 coupled to the dialysis- or to apreparation unit, can be metered in before or after the addition of theacid liquid concentrate.

To allow the escape of air from the container 10 on its filling withwater and/or air, a venting element is provided (not shown in FIG. 1)which can be connected to the dialysis- or the preparation unit. Thisventing element can be formed by a filter, e.g. being arranged in thebag wall or in the region of the connection means 12. This filter shouldbe made such that it allows air and liquid to pass through, but nopowder or granulate so that it cannot unintentionally move out of thecontainer 10.

If a plurality of dialysis treatments are carried out after one anotherwith the same container 10, it is possible to carry out an intermediatedisinfection between the treatments. It is conceivable to do the fillingbefore the purging, with no contamination risk being present since it isthe primary circuit.

FIG. 2 shows an exemplary embodiment of the container 10 in accordancewith the invention with the connection means 12 which serves thecoupling to the coupling means of a preparation- or a dialysis unit.

The arrangement, which can be seen from FIG. 2 represents in a preferredembodiment an arrangement in accordance with the invention for thecoupling of a container 10 to the dialysis- or to a preparation unitwhich is generally marked by the reference numeral 50.

Air and water can be introduced through the port 52 of the dialysis- orthe preparation unit by the connection means 12 to the container 10 andthrough the hose 16 into the lower region of the container 10. For thispurpose, a connection of the port 52 to the connection 120 at thecontainer side takes place.

The container 10 or its connection means 12 is connected via a furthercoupler or connector 122 to the dialysis- or the preparation unit. Thecorrespondingly associated line is marked by the reference numeral 51.

Air is removed from the container 10 through the port or the line 51during the dissolving process or during the filling process of thecontainer 10 with water and air.

Different from the teaching known from EP 1 344 550 B1, the line 52 orthe line 16 in accordance with the present invention does not only servethe supply of water and air, but also the leading off of the dissolvedconcentrate. It is drawn off through the line 16 and the line 52 bymeans of a suitable conveying means, for example by means of a pump, andis then diluted at a suitable point in the dialysis- or in thepreparation unit so that, optionally after adding a base concentrate, afinished dialysis solution can be provided. This means that the flowpath through the connection means and the coupling means as well asthrough hose of the water used for the dissolving at least regionallycorresponds to that via which the liquid concentrate is led off. One andthe same pump can also be used to supply the water, on the one hand, andto lead off the liquid concentrate, on the other hand.

As can be seen from FIG. 2, the ports or the lines 51, 52 have stubsonto which the connectors 120, 122 of the receptacle 10 are placed, ande.g. plugged, so that receiving regions of the connectors 120, 122receive the stubs. For this purpose, recesses or receivers 53, 54 arearranged at the dialysis- or at the preparation unit into which thenamed stubs project and into which the corresponding connectors 120, 122are inserted when the container 10 is coupled. In the coupled state, thestubs project into receivers of the connectors 120, 122 or are leastconnected therewith such that a fluid-tight connection is established.In one embodiment these stubs also provide for the possibility to ventthe container 10 by venting means.

The connector 120 is in fluid communication with the hose 16 and theconnector 122 is in fluid communication a filter of the container 10.Such a connection can, for example, be achieved by a groove or the likein the wall of the connectors 120, 122, as is described in EP 1 344 550B1. A chamber which is likewise described in more detail in EP 1 344 550B1 can be located between the connector 120, 122 and the line 16.

Accordingly, water and air can be supplied to the container 10 and theliquid concentrate can be led off out of the container 10 via the line52 at the unit side and via the connector 120. Air can be removed or canescape from the container 10 via the line 51 at the unit side and theconnector 122.

In the installed state of the receptacle 10, the cover 59 of thedialysis- or of the preparation unit pivotable about the axis 65 is thenfolded down, i.e. after the coupling of the receptacle 10, so that thestubs 70, 71 arranged at the cover 59 press from above onto theconnectors 120, 122 of the connection means 12 and hold them in thecoupled position. If no receptacle is used, the stubs 70, 71 can engageinto the cut-outs 53, 54 so that a fluid-tight connection likewiseresults. A purging process can be carried out in this position of thecover.

The reference numeral 60 finally marks the end region of the container10 which is sealingly connected to the connection element 12.

FIG. 3 shows a first film with the reference film 500 and a second filmof an embodiment of the container 10 with the reference numeral 600. Afolded region which connects the two films 500 and 600 is marked by thereference numerals 700. This folded region 700 can be designed as aseparate part or can be connected in one piece to one of the films 500,600. As can be seen from FIG. 3, the folded region 700 is formed by twolimbs which are arranged acutely to one another, but do not have thesame length.

FIG. 3 furthermore shows the opening process of the container 10 fromthe folded state shown to the left of the arrow and in the unfoldedstate shown to the right of the arrow.

It is achieved by the limbs of the fold region 700 of unequal lengthsthat on the unfolding the center of gravity moves less than with limbsof equal length so that the V-shaped tip of the container 10 shown bythe reference numeral 710 remains at the bottom, which is of importancefor the dissolving process.

The term “film” used within the framework of the present invention is tobe interpreted generally and includes any wall material of the container10. It can be made as elastic, flexible, etc. The films 500, 600 and thefold 700 or the corner region 700 can comprise the same material.

FIG. 4, left hand illustration, shows the container 10 in accordancewith FIG. 3 in a longitudinal sectional representation and in aperspective view. The connection means 12 by means of which thecontainer 10 can be coupled to a dialysis- or to a preparation unit forthe acid concentrate is arranged in the upper region of the container10. This connection means is in fluid-tight connection with the adjacentfilms or wall regions of the container 10.

As can be seen from FIG. 4, a wall of the container 10 is formed by afilm and the other wall of the container 10 by the other film which hasthe fold-like section. It can be seen from the Figures that thecontainer 10 takes up relatively little space in the folded state, buthas a large intake volume for the dry concentrate or for the dissolvedconcentrate in the unfolded state. Provision is made in a preferredembodiment of the invention that the container 10 or its walls is/aremanufactured exactly from two films.

FIG. 5 shows the film web which comprises two rows 800, 900 in a planview. As can be seen from the Figure, the film sections for forming thecontainer walls are formed in trapezoidal shape in a plan view and arearranged in the two webs such that the lower row 900 of the trapezoidalsections is upside down with respect to the upper row 800 of thetrapezoidal sections, i.e. is standing on its head. This allows a goodutilization of the film material.

As can further be seen from FIG. 5, the clippings 1000 are keptrelatively small in this manner and are e.g. likewise not locatedbetween the mutually adjacent trapezoids.

As is marked by the reference symbol A, the welding is produced in onestep in accordance with the shown pattern M and the cutting of the filmstakes place in a step B following it likewise in accordance with thepattern M.

FIG. 6 shows the films 500, 600 which form the container 10 in aperspective representation. As can be seen from FIG. 5 and as indicatedby arrows, the upper one of the films 500 is first folded in step 1 andthen welded to the lower film web 600 in step 2. The step of the cuttingof the two films to produce mutually separate containers 10 is not shownin FIG. 5. The reference numeral 1100 marks the apparatus for weldingthe respective film sections.

In a preferred embodiment of the invention, the individual films areeach multilayer films, e.g. two-layer films. One layer represents asealing layer which has a low melting temperature. The other layer has ahigher melting temperature in respect to this and has a mechanicalstrength or resistance which is good relative thereto.

The use of polyamide (high melting temperature, good resistanceproperties, transparent and visually appealing) and polyethylene (lowermelting temperature, easy to weld) is conceivable. Such a two-layer filmrepresents a good option for manufacturing the container 10 inaccordance with the invention. The thickness of the films is e.g. 200micrometers and the dimensioning of the films is carried out in that thefilled container 10 can take up a volume of 5 liters.

FIG. 7 shows the two films 500, 600 which form the later walls of thecontainer 10 in the left hand illustration. In a first method step, thefilms are rolled off (FIG. 7, left hand illustration). A fold or a kinkis then produced in one of the films 500, as can be seen from FIG. 7,middle and right hand representation. This kink is carried out such thatthe length of the two films in the kinked state of the film 500 issubstantially identical. The region formed by two limbs 501 forms a wallof the container 10; the further walls are formed by the adjacentsections of the film 500 and by the film 600.

Furthermore, as a fifth aspect, the invention relates to a method ofmaking an liquid acid concentrate or a dialysis liquid at leastcomprising step (i):

-   -   (i) mixing the concentrate according to the first aspect or one        of the embodiments described therein with water, optionally in        the presence of a gas such as air.

In one embodiment said mixing is carried out under at least one of thefollowing conditions, e.g. under a combination of conditions 2), 5) and6):

-   -   1) the mixing is carried within the container 10 according to        claim 11 or 12;    -   2) the mixing is carried within the container 10 according to        claim 12;    -   3) the mixing is carried out in the presence of water and air,        wherein water is added to the container 10 with a velocity of        600 to 800 ml/min;    -   4) the mixing is carried out in the presence of water and air,        wherein air is added to the container 10 with a velocity of 1 to        3 l/min;    -   5) the mixing is carried out in the presence of water and air,        wherein water is added to the container 10 with a velocity of        600 to 800 ml/min and air is added to the container 10 with a        velocity of 1 to 3 l/min;    -   6) the mixing is carried out at a temperature of from 50° C. to        65° C., e.g. 55° C. to 60° C.

In one embodiment, said making of the dialysis liquid is completed inless than 10 minutes, e.g. in a time frame of 5 to less than 10, e.g. 7to 9 minutes, in particular in cases where the combination of aboveconditions 2), 5) and 6) is used. This embodiment is particularly suitedto provide a dialysis liquid, such as a liquid acid concentrate in atailor-made form for one treatment of one patient.

In another embodiment said mixing is carried out within the dialysis orpreparation unit at a point in time, where no dialysis takes place.

In a sixth aspect, the present invention furthermore relates to the useof a container 10 in accordance with the present invention formanufacturing an acid liquid concentrate which in turn serves themanufacturing of a dialysis solution, e.g. of a dialysis solution forhemodialysis. In particular under the 5th and 6th aspect, i.e. theprovision of the liquid acid concentrate, the beneficial dissolutionproperties of the dry concentrate play an important role. While duringthe preparation of a dialysis solution directly from a dry concentrate,significantly larger amounts of water are added to the suitable amountof dry concentrate to provide a physiologically acceptable dialysissolution, within the subject invention, the dry concentrate is dissolvedin significantly lower amount of water, i.e. in the range of 1 to 15liters, e.g. 4 to 6 liters of water, as e.g. outlined hereinbefore inrelation to the fourth aspect of the invention.

In a seventh aspect, the invention further relates to the use of an acidliquid concentrate located in a container 10 in accordance with theinvention for manufacturing a dialysis solution, e.g. a dialysissolution, which is used for hemodialysis.

The present invention furthermore relates to a dialysis unit or to apreparation unit, with the preparation unit serving the manufacture of aconcentrate for a dialysis solution. Provision is made in accordancewith the invention that the dialysis- or the preparation unit is coupledto a container 10 in accordance with the invention or is suitable forcoupling to such a container 10.

For further details regarding the sixth and seventh aspect references isagain made to WO 2010/004263.

According to a further aspect, the invention relates to a dialysis orpreparation unit, at least comprising a concentrate for a dialysisliquid according to the first aspect or one of the embodiments describedtherein or the dialysis liquid resulting from the admixture of water tosaid concentrate.

In one embodiment said dialysis or preparation unit comprises means forcontrolling the appropriate mixing of the dry concentrate with the otherconstituents necessary to provide the desired liquid acid concentrate orthe dialysis solution. In one embodiment, said control means are adaptedto also control the flow of water and/or a gas during said mixing.

EXAMPLES

The following dry concentrates including the acid component wereprepared. The components “minors” and “NaCl/dextr.” were respectivelyobtained by a granulation process following EP 0 287 978. The belownumbers (in “g”) are to be understood exemplarily and are intended toillustrate on the basis of this example the respective ratios of theconstituents present in the dry concentrate.

111.50 211.50 311.50 411.50 granules minors MgCl₂, 18.25 18.27 18.3018.32 6H₂O CaCl₂, 39.60 39.64 39.70 39.75 2H₂O KCl 13.39 26.80 40.2653.75 NaCl 31.48 31.52 31.56 31.60 total 102.73 116.24 129.81 143.41powder Citric acid C₆H₈O₇ 34.50 34.54 34.58 34.63 granules NaCl/dextr.NaCl 1049.45 1050.56 1051.92 1053.28 dextrose 179.58 179.77 180.00180.23 total 1229.03 1230.33 1231.92 1233.51

The thus obtained granulates were provided in the form of a bag asdescribed with reference to FIG. 1 and admixed with a total amount ofwater of 4157 g. The resulting liquid concentrate was further dissolvedin the dialysis unit in a ratio of 37 to 1. The water was introducedinto the bag with a velocity of 700 ml/min together with air in anamount of 2 l/min. After around 7 minutes, complete dissolution wasachieved and a dialysis was treatment was conducted. The concentrations(Mmol/ml) within the dialysis solution were as follows:

Citric acid: 1

Cl: 109-111

Ca: 1.5

Mg: 0.5

K: 2 to 4

Na: 103.

The invention claimed is:
 1. A dry concentrate suitable to form a liquid acid concentrate or a part of a liquid acid concentrate usable in dialysis comprising a first component comprising a first granulate comprising a plurality of first granules comprising sodium chloride and glucose, wherein each of said first granules comprises said sodium chloride and said glucose and a second component comprising a second granulate comprising a plurality of second granules, wherein said second granules comprise at least one physiologically acceptable electrolyte, which is different from sodium chloride, or a second component in the form of a powder, wherein said powder comprises at least one physiologically acceptable electrolyte which is different from sodium chloride, and wherein said powder comprises a plurality of fine particles, wherein each particle comprises of one of said at least one physiologically acceptable electrolyte, which is different from sodium chloride; or a mixture of said second granulate and said powder; wherein said dry concentrate is substantially free of a base component that is suitably used in dialysis and wherein the first granulate of the first component or both the first granulate and the second granulate are formed from a granulation process step.
 2. The dry concentrate according to claim 1, wherein the first granulate comprises at least 50 wt-% of first granules, based on the total weight of the first granulate in the dry concentrate, which have an equivalent diameter of above 0.5 to below 12.5 mm.
 3. The dry concentrate according to claim 1, wherein said second component comprises a cation selected from the cations of magnesium, calcium, potassium, or mixtures of two or more thereof; and comprises an anion selected from chloride, acetate, lactate, or mixtures of two or more thereof.
 4. The dry concentrate according to claim 1, further comprising citric acid as a third component.
 5. The dry concentrate according to claim 1, wherein said base component is sodium bicarbonate.
 6. The dry concentrate according to claim 1, wherein the first granulate comprises at least 90 wt-% of first granules, based on the total weight of the first granulate in the dry concentrate, which have an equivalent diameter of above 0.5 to below 12.5 mm.
 7. The dry concentrate according to claim 1, wherein the second component comprises MgCl₂, CaCl₂ and KCl.
 8. The dry concentrate according to claim 1, wherein the first and the second components comprise said first and second granulates.
 9. The dry concentrate according to claim 8, wherein the first granules of the first component exhibit a higher average equivalent diameter than the second granules of the second component.
 10. The dry concentrate according to claim 8, wherein the second granulate comprises at least 50 wt-% of second granules, based on the total weight of the first granulate in the dry concentrate, which have an equivalent diameter of above 1 to below 5 mm.
 11. The dry concentrate according to claim 8, wherein the second granulate comprises at least 90 wt-% of second granules, based on the total weight of the first granulate in the dry concentrate, which have an equivalent diameter of above 1 to below 5 mm.
 12. The dry concentrate according to claim 1, wherein the granulates of the first component or the first and the second components are obtainable via a manufacturing process comprising the following: dry compressing said NaCl and glucose to obtain first compacts, or dry compressing said NaCl and glucose and the at least one physiologically acceptable electrolyte to obtain first and second compacts, wherein said dry compressing of said first and said dry compressing of said second compacts are conducted separately from each other; reducing the size of said first compacts to form the first granulate comprising the plurality of first granules, or reducing the size of said first and second compacts to form the first and second granulates comprising a plurality of first and second granules.
 13. The dry concentrate according to claim 12, wherein the dry compressing comprises passing the NaCl and glucose or the NaCl glucose and the at least one physiologically acceptable electrolyte under pressure between two rolls with parallel axes, which are driven in mutually counter-rotating rotation sense; wherein reducing the size of said first and second compacts is achieved by grinding, milling, crushing, or a combination of two or more thereof; and wherein said dry compressing and reduction of size are carried out continuously.
 14. A container comprising at least the dry concentrate according to claim
 1. 15. A dialysis or preparation unit, wherein the preparation unit serves to prepare a liquid concentrate to be used for the preparation of a dialysis solution, comprising at least one concentrate according to claim 1; or a container comprising at least the dry concentrate, wherein the container is connected to the dialysis or preparation unit.
 16. A liquid acid concentrate formed from the dry concentrate according to claim
 1. 17. A process for the preparation of the dry concentrate according to claim 16 comprising the following: dry compressing said NaCl and glucose to obtain first compacts, or dry compressing said NaCl and glucose, and the at least one physiologically acceptable electrolyte to obtain first and second compacts, wherein said dry compressing of said first and said dry compressing of said second compacts are conducted separately from each other; reducing the size of said first compacts to form the first granulate comprising the plurality of first granules, or reducing the size of said first and second compacts to form the first and second granulates comprising a plurality of first and second granules.
 18. The process according to claim 17, wherein said manufacturing process further comprises sieving of said granulates obtained by reducing the size of said compacts through at least two sieves.
 19. A method of preparing a liquid acid concentrate which in turn serves the preparation of a dialysis solution, at least comprising (i): (i) mixing the concentrate according to claim 1 with water.
 20. A method of claim 19, wherein (i) is carried out in the presence of a gas. 